Traditional chemotherapeutic drugs treat cancer by inhibiting DNA synthesis or inhibiting cell division. Practice shows that these compounds also have certain toxicity to normal cells. However, the molecular targeted therapies (MTTs) developed in the past one or two decades can greatly lower the toxicity of drugs to normal cells. Imatinib, which is used as therapy of Chronic Myeloid Leukemia (CML), has become one of the breakthrough milestones in the field (The Lancet Oncology, 2008, 600).
Epidermal growth factor receptor (EGFR/ErbB1/HER1 a transmembrane protein having a molecular weight of approximately 170 kD, is a member of receptor tyrosine kinase ErbB Family. This family includes members such as EbB2/HER2/Neu, ErbB3/HER3, ERbB4/HER4 and the like. After a ligand that is similar to EGF (e.g. EGF and TGF-α) conjugates to the receptor, dimerization occurs, thus activating a signaling pathway within a variety of downstream cells, e.g. PI3K/Akt, MAPK, signal transducers and activators of transcription (STAT), and the like. These signaling pathways are involved in the significant physiological processes, such as regulation, migration, cell death, cell growth, and the like. (Expet. Opin. Emerg. Drugs, 2010, 185).
Many studies have shown that a variety of tumor cells are directly related to over-expression of EGFR and over-expression of EGFR ligand (Curr. Drug Targets, 2001, 2, 117-133). The growth of multiple types of tumor cells can be effectively controlled by inhibiting the conjugation between EGFR and its ligand as well as activity of EGFR tyrosine kinase. There are a variety of drugs to inhibit EGFR for treating cancer currently in clinical trials. These cancers include lung cancer, colon cancer, gastric cancer, breast cancer, ovarian cancer, leukemia, prostate cancer, uterine cancer, pancreatic cancer, liver cancer, bladder cancer, renal cancer, thyroid cancer, brain cancer, head and neck cancer, and the like. (Cell. Signal., 2010, 22, 984-1002).
The research and development of antitumor drugs against EGFR is mainly concentrated on the antibody drug and small molecule compounds that inhibit the tyrosine kinase receptor. The first generation of small molecule compounds are reversible kinase inhibitors, such as Astra-Zeneca's Gefitinib (U.S. Pat. No. 5,616,582), Roche's Erlotinib (U.S. RE41,065) and GlaxoSmithKline's (GSK) Lapatinib (U.S. Pat. No. 6,391,874), etc. The second generation of small molecule compounds are irreversible inhibitors, such as Boehringer Ingelheim's BIBW2992 (Oncogene, 2008, 27, 4702-4711) and Pfizer's Neratinib (Cancer Res. 2004, 64, 3958-3965), which are in Phase III clinical trials. Conjugating receptor kinase via covalent bonds, these compounds are better able to inhibit EGFR and related kinases, and demonstrate significantly higher inhibiting effectiveness, especially for cancer cells containing mutant receptor tyrosine kinases.
The it has been difficult to develop therapeutic drugs that target EGFR due to the secondary mutations in EGFR that cause drug resistance. in clinical settings, it is difficult to choose the right drug because of the diversity of kinase mutations. However, genetic testing and diagnostic tools, developed in recent years, have facilitated selecting drugs more effectively. It has become an inevitable development in direction of molecular targeted cancer treatment in the past one or two decades that treating cancer patients having different mutations with different types of drugs is necessary. Therefore, the development of more innovative drug molecules, that meet the medical need of different patients by providing more personalized cancer treatment drugs are desired.